Neuroprotective effects of resistance physical exercise on the APP/PS1 mouse model of Alzheimer's disease.

Introduction: Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to AD. Most studies, however, have been conducted with aerobic exercises, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD. Similar to AD patients, double-transgenic APPswe/PS1dE9 (APP/PS1) mice exhibit Αß plaques in the cortex and hippocampus, hyperlocomotion, memory deficits, and exacerbated inflammatory response. Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. Methods: For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (CTRL), were distributed into three groups: CTRL, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aß plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay. Results: APP/PS1 transgenic sedentary mice showed increased hippocampal Aß plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aß alterations to the CTRL levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Despite these alterations, no memory impairment was observed in APP/PS1 mice in the novel object recognition test. Discussion: Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

Deep brain stimulation of the anterior thalamus attenuates PTZ kindling with concomitant reduction of adenosine kinase expression in rats.

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging therapy to provide seizure control in patients with refractory epilepsy, although its therapeutic mechanisms remain elusive. OBJECTIVE: We tested the hypothesis that ANT-DBS might interfere with the kindling process using three experimental groups: PTZ, DBS-ON and DBS-OFF. METHODS: 79 male rats were used in two experiments and exposed to chemical kindling with pentylenetetrazole (PTZ, 30 mg/kg i.p.), delivered three times a week for a total of 18 kindling days (KD). These animals were divided into two sets of three groups: PTZ (n = 26), DBS-ON (n = 28) and DBS-OFF (n = 25). ANT-DBS (130 Hz, 90 µs, and 200 µA) was paired with PTZ injections, while DBS-OFF group, although implanted remained unstimulated. After KD 18, the first set of PTZ-treated animals and an additional group of 11 naïve rats were euthanized for brain extraction to study adenosine kinase (ADK) expression. To observe possible long-lasting effects of ANT stimulation, the second set of animals underwent a 1-week treatment and stimulation-free period after KD 18 before a final PTZ challenge. RESULTS: ANT-DBS markedly attenuated kindling progression in the DBS-ON group, which developed seizure scores of 2.4 on KD 13, whereas equivalent seizure scores were reached in the DBS-OFF and PTZ groups as early as KD5 and KD6, respectively. The incidence of animals with generalized seizures following 3 consecutive PTZ injections was 94%, 74% and 21% in PTZ, DBS-OFF and DBS-ON groups, respectively. Seizure scores triggered by a PTZ challenge one week after cessation of stimulation revealed lasting suppression of seizure scores in the DBS-ON group (2.7 ± 0.2) compared to scores of 4.5 ± 0.1 for the PTZ group and 4.3 ± 0.1 for the DBS-OFF group (P = 0.0001). While ANT-DBS protected hippocampal cells, the expression of ADK was decreased in the DBS-ON group compared to both PTZ (P < 0.01) and naïve animals (P < 0.01). CONCLUSIONS: Our study demonstrates that ANT-DBS interferes with the kindling process and reduced seizure activity was maintained after a stimulation free period of one week. Our findings suggest that ANT-DBS might have additional therapeutic benefits to attenuate seizure progression in epilepsy.

Male rats are more vulnerable to pentylenetetrazole-kindling model but females have more spatial memory-related deficits.

Epilepsy is the most common neurological condition worldwide and is largely associated with memory impairment, both in human as well as animal models. Furthermore, differences in seizure onset and severity have already been observed between the sexes. The induction of epilepsy through multiple systemic injections of pentylenetetrazole (PTZ), a protocol known as chemical kindling, is a well-established tool for studies regarding epileptogenesis, as well as the efficacy of antiseizure medication. The aim of this study was to compare possible sex-related differences in seizure severity, memory, neuronal damage as well as the effects of the estrous cycle on seizure severity. Male (n = 10) and Female (n = 11) animals received 30 mg/kg i.p. injections three days a week for 6 weeks and, after the last application, were tested for short and long-term memory. Control, Male (n = 8) and Female (n = 5) groups did not receive PTZ injections. Although PTZ did not promote important changes into the estrous cycle phases throughout the entire experiment, female animals presented lower seizure scores but had both short and long-term memory impairments associated with cell loss in the hippocampus and anterior cingulate area. Male rats presented higher seizure scores associated with pronounced cell loss, but only long-term memory deficits. Our results demonstrate that the PTZ kindling protocol results in higher seizure scores with increased vulnerability in male rats, but female rats displayed more intense memory deficits.

Partial protective effects of cannabidiol against PTZ-induced acute seizures in female rats during the proestrus-estrus transition.

Approximately 70% of women with epilepsy experience additional challenges in seizure exacerbation due to hormonal changes, particularly during fluctuations of estrogen-progesterone levels in the menstrual cycle, which is known as catamenial epilepsy. In animal models of epilepsy, a sustained increase in seizure frequency has been observed in female rats during the proestrus-estrus transition when estrogen levels are high and progesterone levels are low resembling catamenial epilepsy. Cannabidiol (CBD) has been proposed to have anticonvulsant and anti-inflammatory effects, able to decrease seizure duration and increase seizure threshold in rats with epilepsy. However, most studies have used males to investigate the pharmacological effects of CBD on seizures, and the neuroprotective effects of CBD against seizures exacerbated by hormonal fluctuations in females are still little explored. Given this scenario, the aim of the present study was to investigate whether CBD would protect against acute seizures induced by pentylenetetrazole (PTZ) in female rats during a pro-convulsant hormonal phase. Therefore, CBD (50 mg/kg) or saline was administered during the proestrus-estrus transition phase, 1 h prior to induction of seizures with PTZ (60 mg/kg), and the following parameters were recorded: duration, latency to first seizure, as well as percentage of convulsing animals (incidence), mortality, and severity of seizures. Brains were processed for immunohistochemistry for microglial cells (Iba-1), and blood was collected for the analysis of cytokines (IL-1ß, IL-6, IL-10, and TNF-α). Cannabidiol pre-treated rats showed a significant reduction in duration and severity of seizures, and IL-1ß levels, although the latency, incidence of seizures, and mortality rate remained unchanged as well the quantification of microglia in the selected areas. Therefore, acute administration of CBD in a single dose prior to seizure induction showed a partial neuroprotective effect against seizure severity and inflammation, suggesting that female rats in the proconvulsant phase of proestrus-estrus have a low seizure threshold and are more resistant to the anticonvulsant effects of CBD. It appears that other doses or administration windows of CBD may be required to achieve a full protective effect against seizures, suggesting that CBD could be used as an adjunctive therapy during fluctuations of estrogen-progesterone levels. In this sense, considering the hormonal fluctuation as a seizure-potentiating factor, our study contributes to understand the anticonvulsant activity of CBD in females in a pro-convulsant hormonal phase, similar to catamenial seizures in humans.

Distinct Effects of the Hippocampal Transplantation of Neural and Mesenchymal Stem Cells in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe disabling condition with no cure currently available, which accounts for 60-70% of all dementia cases worldwide. Therefore, the investigation of possible therapeutic strategies for AD is necessary. To this end, animal models corresponding to the main aspects of AD in humans have been widely used. Similar to AD patients, the double transgenic APPswe/PS1dE9 (APP/PS1) mice show cognitive deficits, hyperlocomotion, amyloid-ß (Αß) plaques in the cortex and hippocampus, and exacerbated inflammatory responses. Recent studies have shown that these neuropathological features could be reversed by stem cell transplantation. However, the effects induced by neural (NSC) and mesenchymal (MSC) stem cells has never been compared in an AD animal model. Therefore, the present study aimed to investigate whether transplantation of NSC or MSC into the hippocampus of APP/PS1 mice reverses AD-induced pathological alterations, evaluated by the locomotor activity (open field test), short- and long-term memory (object recognition) tests, Αß plaques (6-E10), microglia distribution (Iba-1), M1 (iNOS) and M2 (ARG-1) microglial phenotype frequencies. NSC and MSC engraftment reduced the number of Αß plaques and produced an increase in M2 microglia polarization in the hippocampus of APP/PS1 mice, suggesting an anti-inflammatory effect of stem cell transplantation. NSC also reversed the hyperlocomotor activity and increased the number of microglia in the hippocampus of APP/PS1 mice. No impairment of short or long-term memory was observed in APP/PS1 mice. Overall, this study highlights the potential beneficial effects of transplanting NSC or MSC for AD treatment.

The neural response to deep brain stimulation of the anterior nucleus of the thalamus: A MEMRI and c-Fos study.

BACKGROUND: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level. OBJECTIVE: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE). METHODS: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 µA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections. RESULTS: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry. CONCLUSION: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.